Process for 2(2-(1,3-diazacycloalk-2-enyl))benzophenone derivatives and 1,3-diazacycloalkenyl(2,1-a)isoindole derivatives

ABSTRACT

Novel 2(2-(1,3-diazacycloalk-2-enyl))benzophenone compounds and novel 1,3-diazacycloalkenyl(2,1-a)isoindole compounds having useful analgesic and psychostimulant properties are prepared inter alia by condensation of o-benzoylbenzaldehydes with aliphatic diamines.

United States Patent Metlesics et al.

[4 1 June 10, 1975 PROCESS FOR 2 2-( 1 ,3-DIAZACYCLOALK-2- ENYL)]BENZOPHENONE DERIVATIVES AND 1,S-DIAZACYCLOALKENYL[2,1- A]ISOINDOLEDERIVATIVES Inventors: Werner Metlesics, Clifton; Leo

Henryk Sternbach, Upper Montclair, both of NJ.

Assignee: Hoffmann-La Roche Inc., Nutley,

Filed: May 18, 1967 Appl. No.: 639,315

Related US. Application Data Continuation-impart of Ser. No. 626,965,March 30, 1967, abandoned.

US. Cl. 260/239 BC; 260/251 A; 260/251 R; 260/3096; 260/3265 B; 260/591;260/618 B; 424/251; 424/273; 424/274 [51] Int. Cl.. C07d 51/28; C07d57/14; C07d 53/02 [58] Field of Search... 260/326.5 B, 239 BC, 251 A,260/251 R, 309.6

[56] References Cited UNITED STATES PATENTS 3,379,733 4/1968 Houlihan260/3261 Primary Examiner-Henry R. Jiles Assistant Examiner-Bernard I.Dentz Attorney, Agent, or FirmSamuel L. Welt; Bernard S. Leon; WilliamG. lsgro [5 7] ABSTRACT 5 Claims, N0 Drawings PROCESS FOR 2 [2-(1,3-DIAZACYCLOALK-2- ENYL) BENZOPHENONE DERIVATIVES AND Compounds offormula I can undergo a prototropic shift to form compounds of theformula 1,3-DIAZACYCLOALKENYL[2,1-A]ISOINDOLE DERIVATIVES 5 R1 4\ 1 L\ li RELATED APPLICATIONS RA This application is a continuation-in-part ofApplica-, l 03; tion Ser. No. 626,965 filed Mar. 30, 1967 now aban- 1Odoned. l 5 i R 1 A 3 BRIEF SUMMARY OF THE INVENTION M This inventionrelates to a novel class of 2[2-(1,3- Adiazacycloalk-2-enyl)]benzophenones and novel 1,3- 15 wherein R R R Rand B each have the same meandiazacycloalkenyl[2,l-a]isoindoles, novelprocesses ing as hereinabove. and intermediates for the preparation ofsaid novel The invention includes both tautomeric isomers as productsand derivatives thereof and to the use of said well as mixtures thereof.Tautomeric mixtures can be novel compounds as pharmaceuticals. Moreparticurepresented schematically as Dl R1 1 I B i \l I (J 32 C 0 R i\Jsl R3 I i a I II larly, the invention in its product aspect relates tonovel wherein R R R R and B each have the same meancompounds of theformula wherein B represents an alkylene chain of 2 to 4 carbon atoms inwhich one or more of the hydrogens can be replaced by lower alkyl; and RR R and R are each independently selected from the group consisting ofhydrogen, halogen, lower alkyl, lower alkoxy, hydroxy andtrifluoromethyl and pharmaceutically acceptable acid addition saltsthereof.

ing as hereinabove.

DETAILED DESCRIPTION In one product aspect this application pertains tothe novel compounds of formulas I and II and derivatives thereof. Ofparticular interest are the compounds of formulas I and II wherein Brepresents the group and R and R are each independently hydrogen orlower alkyl, i.e., compounds of the formulas wherein R R R and R eachhave the same meaning as hereinabove; and R and R are each independentlyhydrogen or lower alkyl and their pharmaceutically acceptable acidaddition salts and tautomeric mixtures.

Compounds of formulas l-a and II-a wherein R R R and R are eachhydrogen, i.e., compounds of the formulas 3 4 N- I Hz \N-CHZ /C\ (|;H2

I-b II-b wherein R and R each have the same meaning as In one of itsprocess aspects this application pertains hereinabove and theirpharmaceutically acceptable to the preparation of compounds of formulasI, II and acid addition salts and tautomeric mixtures constitute II-daccording to the following reaction sequence. a preferred group. p

In another product aspect this application pertains to OH OH the mixedethers obtained from compounds of formula R1 2 II and lower alkanols,i.e., compounds of the formula R2 HOH II-d R1 CHO sfl 4 wherein R R R Rand B each have the same mean- Rs ing as hereinabove; and R is loweralkyl. 4 I

In still another product aspect this application per- IV" tains to novelintermediates which will be more fully described with reference to theseveral processes for the preparation of compounds of formulas I and II.

N R c B B1 c er- N/ w B R2 CH C OOH R III II-c R1 R1 B I 4 II 4 II-dwherein R R R R,,, R and B each have the same meaning as hereinabove.

The diol starting materials of formula V are known compounds or arereadily obtainable in analogy to the preparation of the known compounds.The diol starting materials can be readily converted to the dicarbonylintermediates of formula IV by oxidation techniques which are known perse such as, for example, using selenium dioxide and the like, as theoxidizing agent or by employing other oxidizing systems such as chromiumtrioxide in pyridine.

Treatment with an oxidizing agent can be conveniently carried out in anorganic solvent such as, for example, dimethylformamide,dimethylsulfoxide; hydrocarbon solvents such as benzene, toluene;alkanols, e.g., the lower alkanols, methanol, ethanol, etc.; acetic acidand the like. The oxidation reaction is preferably carried out at anelevated temperature suitably at a temperature between about roomtemperature and about 150C.

The intermediates of formula IV are themselves novel compounds and thusalso constitute part of this invention. The intennediates of formula IVare readily condensed with diamines of the formula wherein B has thesame meaning as hereinabove by mixing the components or by reacting themin the presence of an organic solvent such as benzene, toluene; alcoholssuch as lower alkanols and the like. The condensation is convenientlycarried out at room temperature or above, preferably at a temperaturebetween about 20C. and 150C. Alternatively, the diamine reactant offormula XII can be employed as a salt thereof in which case the reactionis conducted by heating the mixture of reactants to a melt.

The reaction products, i.e., the compounds of formula III, can bereadily oxidized, for example, by treatment with an oxidizing agent suchas hydrogen peroxide or by exposure to gaseous oxygen at roomtemperature to give the peroxides of formula II-c which are readilyreduced to the corresponding end products. The oxidation is convenientlycarried out in an organic solvent such as alcohols, dimethylformamide,etc. at room temperature. Higher or lower temperatures, e.g., betweenabout 20C. and 100C, can also be employed.

Since the peroxide intermediates readily undergo reduction, the reactionmixture obtained upon treatment of a compound of formula III with anoxidizing agent will ordinarily contain the end products along with theperoxide intermediate of formula Il-c. Complete reduction of theperoxide can be accomplished without separating it from the reactionmixture and, in a preferred embodiment, the oxidation product issubmitted directly to treatment with a reducing agent. If desired,

however, the peroxide intermediate of formula II-c can be separated fromthe reaction mixture obtained upon treatment of a compound of formulaIII with an oxidizing agent by any of the usual techniques, e.g.,chromatographic separation, fractional crystallization, etc.

The reduction of the peroxide is conveniently carried out by employingany reducing agent conventionally used for the reduction of peroxidessuch as sodium sulfite, trialkylphosphite, etc. preferably in thepresence of an organic solvent such as an alcohol, e.g., methanol,ethanol, etc.; dimethylformamide and the like, or when using a salt ofthe peroxide, the reduction can be carried out in an aqueous solvent,e.g., in an aqueous alcoholic solvent. The reduction is suitably carriedout at room temperature or above, preferably at a temperature betweenabout 20C. and C.

As noted above, the hydroxyl proton of a compound of formula II canundergo a prototropic shift to form the corresponding isomeric endproduct of formula I. In solution the product obtained upon oxidationand reduction of an intermediate of formula III will ordinarily be amixture of the tautomeric forms I and II. The relative amounts of theisomeric forms present is dependent upon such factors as the solventsystem employed, the pH of the medium and the particular product, i.e.,the meaning of B, R R R and R in formulas l and II. For example, in asolution of chloroform the product obtained upon oxidation and reductionof 2,3- dihydro-S-phenyl-Sl-I-imidazo[2,1-a]isoindole contains a mixtureof the isomers 2,3-dihydro-5-hydroxy-5-phenyl-5l-I-imidazo[2,l-a]isoindole and2-(2-benzoylphenylj-Z-imidazoline in a ratio of about 1:1. The acidaddition salts isolated in the ordinary manner from the reaction productof the oxidation and reduction of 2,3- dihydro-5-phenyl-5H-imidazo[2, l-a]isoindole are ordinarily obtained as structure I.

Compounds of formula lI-d are prepared from compounds of formula II bytreating an acid addition salt, e.g., the hydrochloride, hydrobromide orthe like, of a formula II compound with a lower alkanol preferably at anelevated temperature. The etherification can be suitably carried outusing the lower alkanol as solvent or in the presence of an inertorganic solvent such as ether and the like and preferably at atemperature between about room temperature and the reflux temperature ofthe reaction mixture, i.e., up to about C.

The novel compounds of formula lI-d as well as the intermediates offormulas Il-c and III are obtained as racemates. It is intended toinclude in this invention all of the stereoisomeric forms whether theyare obtained as racemic mixtures or as the separated optically activeantipodes.

The intermediates of formulas III and 11-0 are also novel compoundswhich constitute part of this invention. Compounds of formula III are,in addition to being useful as intermediates in the preparation ofcompounds of formulas I and II, also useful as psychostimu lant,anti-inflammatory and anti-pyretic agents.

Alternatively, the compounds of formulas III, II and I can be preparedaccording to the following reaction scheme:

-Continued NHa-JB-NH a a V N a NZ-I2 R2 R2 VIII L %N R1 C B C B l ooH Q?8 R4 III II-c A N DQC R R2 c=o I 4 II wherein R R R R and B each havethe same meaning as hereinabove.

According to one alternative synthesis outlined above the intermediatesof formula III are prepared by cyclization of a phthalimidine of formulaVI. The cyclization of a phthalimidine of formula VI to form anintermediate of formula III is readily accomplished by treatment with aLewis acid such as titanium chloride, boron trifluoride and the like.The oxidation and reduction of the formula II intermediates to form thedesired end products is accomplished by the procedures de scribed above.

The reaction with Lewis acid is preferably carried out in the presenceof an inert organic solvent, e.g., hydrocarbon solvents such as toluene,xylene and the like, and preferably at an elevated temperature suitablyat the reflux temperature of the solvent employed. A preferredtemperature range for the cyclization of the phthalimidines is atemperature between about 50C. to about 200C. The phthalimidineintermediates of formula VI are prepared by condensing a 3- 7 poundswhich'are readily accessible in analogy to the phenylphthalide offormula VI] with a diamine of formula XII. The 3-phenylphthalides offormula W1 and the diamines of formula X employed as starting materi alsare known compounds or analogs of known comknown compounds.

The preparation of the formula VI intermediates is catalyzed by salts oforganic bases such as pyridine, trialkylamine, quinoline,ethylenediamine, etc., with acids such as an organic acid, a mineralacid, e.g., sulfuric acid, hydrohalic acid, phosphoric acid, perchloricacid, etc., or a Lewis acid such as zinc chloride, aluminum chloride,etc. Preferred catalysts for the reaction are the salts ofethylenediamine and pyridine such as pyridinium hydrochloride and thelike. It is preferred to carry out the reaction with an excess of theethylenediamine reactant as solvent. However, inert organic solventssuch as alcohols, e.g., methanol, ethanol, etc.; hydrocarbons, e.g.,benzene, toluene, etc.; ethers, e.g., tetrahydrofuran, dioxane, etc.,can also be employed. The reaction is carried out at an elevatedtemperature,

formula Rs r wherein R and R each have the same meaning as hereinabove;and Z is Li, MgBr, Mgl, MgCl or the like.

The reaction with a phenyl-lithium derivative of formula XI can beconveniently carried out in the presence of an inert solvent at aboutroom temperature. Higher or lower temperatures suitably in the range ofabout C. to about 100C. can also be employed. Suitable solvents that canbe utilized are, for example, the hydrocarbons such as benzene, toluene,xylene, etc., ethers, and the like or mixtures of such solvents.

The diazacycloalkenylisoindolone intermediates of formula VIII are alsonovel compounds and thus constitute a part of this invention. They arereadily prepared by the condensation of a phthalaldehydic acidderivative of formula lX-with an alkylene diamine of formula XII. Thecondensation reaction is conveniently carried out in the presence of aninert organic solvent and preferably at an elevated temperature.Suitable temperatures for carrying out the condensation reaction aretemperatures between about C. and about 100C. or the boiling point ofthe reaction mixture. As solvent for the condensation there can besuitably employed any of the usual organic solvents such as alcohols,hydrocarbons, ethers, etc.

The phthalaldehydic acid derivatives of formula IX are known startingmaterials or analogs of known compounds readily obtained by knownprocesses.

In still another alternative process, the end products of formula I canbe obtained by oxidation of a lphenyl-2-aminoalkylisoindoline derivativeas outlined below:

R1 CH2X 2 s wherein B, R R R and R are as defined hereinabove; and X ishalogen, preferably chlorine, iodine or bromine or other similar leavinggroups such as mesyloxy, tosyloxy and the like.

The oxidation is accomplished by treating with an oxidizing agent suchas gaseous oxygen or chemical oxidants such as chromium trioxide inacetic acid and the like.

The reaction is preferably carried out in the presence of an organicsolvent such as, for example, hydrocarbon solvents, e.g., benzene,toluene or the like; alkanoic acids, e.g., acetic acid, propionic acid,etc.; ethers, alcohols and solvents such as dimethylformamide, etc. Thereaction can be suitably accomplished at room temperature or at anelevated temperature, preferably at a temperature between about 20C. andC. The l-phenyl-2-aminoalkylisoindoline intermediates are prepared fromthe diols of formula V via a diester of formula V-a. The diesters areobtained by the usual techniques for esterification, e.g., treating thediol with one of the ordinary esterifying agents such as a halo acid andhalides such as phosphorous halide, thionyl halide, tosyl halide, etc.The diester of formula V-a is in turn converted to the 1-phenyl-2-aminoalkylisoindoline intermediate of formula VI by condensing with adiamine of formula XII.

The reaction with diamine is conveniently carried out by adding thediester of formula V-a to the diamine at room temperature. Preferably,there is employed a large molar excess of diamine. The reaction can alsobe carried out at temperatures above or below room temperature, althoughfor practical reasons it is preferred to operate at a temperaturebetween about 0C. and

100C. The reaction is suitably carried out in the presence of an organicsolvent such as, for example, benzene, methylene chloride, ether,tetrahydrofuran and the like; or, in the case where either or both ofthe reactants are liquid under the conditions employed in the reaction,the reaction is conveniently carried out in the absence of a solvent.

The preparation of the 1-phenyl-2- aminoalkylisoindolines of formula VIdoes not constitute part of this invention and is given here for thesake of completeness only.

As used throughout this application the term lower alkyl denotesstraight and branched chain hydrocarbons containing 1 to 6 carbon atomssuch as methyl,

ethyl, propyl, isopropyl, butyl, sec.-butyl, t.-butyl and the like. Theterm lower alkoxy denotes-lower alkylether groups wherein the alkylgroups is as defined above. The term halogen as used herein includes allfour halogens, i.e., chlorine, bromine, iodine and fluorme.

Suitable salts of the compounds of formula I are prepared from nontoxicorganic and inorganic acids. Suitable organic acids are, for example,maleic acid, fumaric acid, ascorbic acid, tartaric acid, salicylic acid,succinic acid, citric acid and the like. Suitable inorganic acids are,for example, the hydrohalic acids, elgl, hydrochloric acid andhydrobromic acid; sulfuric acid, sulfamic acid, phosphoric acid, etc.The acid addition salts are readily prepared by the usual techniques forthe preparation of acid addition salts which are readily" apparent tothose skilled in the art.

As has been indicated hereinabove the novel end products of thisinvention, i.e., the compounds of for :20

mula I and their pharmaceutically acceptable acid addition salts and thecompounds of formula lI-d and their pharmaceutically acceptable acidaddition salts, are useful aspsychostimulants. When administered, forexample, orally, to animals such as mice they produce a direct-actingstimulant effect of long duration in single doses in amounts rangingfrom .03 mg/kg to 50 mg/kg. By way of illustration the compound ofExample 10, 2-(2-benzoylphenyl)-2-imidazoline, which has an LD in miceof 200 mg/kg p.o.; 130 mg/kg s.c.; 77 mg/kg i.p.; and 37 mg/kg iv (Proc.Soc. Exptl. Biol. Med., Vol. 57, page 261 reversed the hypothermiainduced by reserpine in mice at a dose of mg/kg s.c. (Med. Pharmacol.Exp, Vol. 12, pages 226-232,

1965); prevented the ptosis induced by tetrabenazene' in mice at .06mg/kg p.o. (Pletscher et al., Progress.

pounds of formuls l and ll-d, the compound of Example 21,2,3,4,5-tetrahydro-7-hydroxy-7-phenyl-7I-ldiazepino-[2,l-a]isoindole,which has an LD of 40 mg/kg i.v., prevented the ptosis induced bytetrabenazene at 0.4 mg/kg. p.o.; reversed the hypothermia andhypometabolic effects induced by reserpine (10 mg/kg s.c.) in mice at 25mg/kg p.o.; and potentiated the effects of DOPA in mice at a dose of 7.5mg/kg i.p. The

' compounds of this invention thus demonstrate a pattern of activityassociated with anti-depressants of known clinical efficacy and aresimilarly useful as psychostimulants in the treatment of depressedstates, for

pounds of formulas I and II-d are also useful as analgesic agents. Byway of example, 2-(2-benzoylphenyl)-2- imidazoline, when submitted tostandard pharmacological tests for for analgesic properties, exhibitedmarked activity in the writhing test in mice at doses of 30.8

mg/kg p.o. and 5 mg/kg so. and anti-pyretic activity in rats at doses of6.25 to mg/kg p.o. The compound 7 also showed potent anti-inflammatoryactivity in the inflamed rat foot test at 6.25 mg/kg p.o. and antiedemaactivity in the Carrageenan anti-edema rat paw test at 6.25 mg/kg p.o.In the unanesthetized cat test for muscle relaxants the compound wasactive at a dose of 2.5 mg/kg p.o. Based on the foregoingpharmacological tests in animals, the analgesic properties of the novelend products of this invention and particularly those of2-(2-benzoylphenyl) 2-imidazoline can be likened to the analgesicproperties of phenylbutazone which is well known for its therapeuticuses and properties.

Drug Research, Vol. 11, page 417, 1960); reversed the reserpine (10mg/kg s.c.) induced sedation in mice by increasing their locomotoractivity at doses of 25-50 mg/kg p.o. (Med. Pharmacol. Exp., Vol. 12,pages 226-232, 1965); and potentiated the effects of B-(3,4-dihydroxyphenyl)-a-alanine (DOPA) in mice at a dose of 6.25 mg/kg i.p.(Arc. Exp. Path. and Pharm., Vol. 140, page 237). The compounds of thisinvention have psychostimulant effects qualitatively similar in manyrespects to those of imipramine and amphetamine which are well-known fortheir therapeutic uses nd properties. Among other illustrative compoundsof formulas I and II-d which have been similarly tested and found to bequalitatively similar to 2-(2-benzoylphenyl)-2-imidazoline, there can benamed by way of exemplification the following:

5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5l-I- imidazo[2, l -a]-isoindole; 2,3-dihydro-5-hydroxy-5-(4-methoxyphenyl)-5H-imidazo[2,l-a]-isoindole; and2,3-dihydro-5-methoxy-5-phenyl-5l-I-imidazo 2, l

a]isoindole. The activity of the claimed compounds of formulas I andII-d first demonstrated by pharmacological evaluation in warm-bloodedanimals as indicated herein permits their use in therapy in the samegeneral manner as imipramine or amphetamine, which latter compoundsexhibit psychostimulant activity in the DOPA potentiation test at dosesof 10 mg/kg i.p. and 1.0 mg/kg i.p. respectively and in the ptosisprevention test at doses of 60 mg/kg and 7.5 mg/kg respectively. As afurther illustation of the psychostimulant activity of the com-Compounds of formulas I and II-d are also useful as an- 7 orexigenicagents owingto their markedactivity in the I 4-hour anti-obesity test inrats wherein compounds of this class have demonstrated activityqualitatively similar to amphitamine. Compounds of this series have alsodemonstrated useful cardiovascular properties. For example,2-(2-benzoylphenyl)-2-imidazoline in dogs at 4 mg/kg iv. produced anincrease in blood pressure of 10 mm. Hg after 2 minutes followed bygradual increase to 25 mm. Hg.

Compounds of formula I have also been found to be active as anti-fungalagents. For example, they have been found to be active in vitro inCandida albicans, Microsporum audouini and Trichlophyton mentagrophytes.Accordingly, these compounds can be employed as anti-fungal agents inthe treatment of pathogenic diseases caused bfy these organisms. Theycan, for example, be employed in the treatment of infectious fungaldiseases such as moniliasis and dermatomycoses. For the treatment offungal infections the compounds of formula I can be employed by applyinga suitable composition containing about 0.1 mg. to about 5 g. of activematerial over the site of the infection. Suitable compositions areprepared by embodying a compound of formula I or a pharmaceuticallyacceptable salt thereof in a conventional carrier suitable for topicaladministration.

The novel end products of this invention, i.e., the compounds offormulas I and lI-d are mostly white crystalline odorless solids meltingat temperatures in the order of 200C. They have basic properties and canbe conveniently prepared in the form of their acid addition salts.Suitable salts are prepared as described hereinabove. The salts arecharacteristically white crystalline odorless solids soluble in waterand have good stability under ordinary conditions.

The compounds of formulas I and II-d, preferably in the form of theiracid addition salts can be formulated into preparations suitable foradministration by enteral or parenteral routes. They can be embodied inpharmaceutical unit dosage forms containing from about 0.5 mg. to about100 mg. of active material, i.e., a compound of formulas I or II-d or asalt thereof. Parenteral formulations will ordinarily contain less ofthe active substance than compositions intended for enteral, e.g., oral,administrationfFor oral administration the products of this inventioncan be prepared as tablets, capsules and the like containing about to 50mg. of active material. Formulations suitable for oral administra-. tionmay be such as to provide either immediate, or in the alternative,sustained release of the active drug. In general, the formulations willbe prepared with pharmaceutically acceptable adjuvant materialscomprising steel may also be used), mixed well and cooled to 45C.

2. 2-(2-Benzoylphenyl)-2-imidazoline, which had been reduced to a finepowder with no lumps, was added and stirred until completely anduniformly dispersed.

3. The mixture was poured into suppository molds to yield suppositorieshaving an individual weight of 1.3 grams.

4. The suppositories were cooled and removed from molds. They wereindividually wrapped in wax paper for packaging. (Foil may also beused.)

Capsule Formulation Per Ca sule 2-( 2-benzoylphenyl )-2-imidazolineLactose Corn Starch Talc 25 mg. 158 mg. 37 mg. 5 mg Total Weight 255 mg.

PROCEDURE Parenteral Formulation Per cc.

2-(Z-benzoylphenyl)-2-imidazoline 2.5 mg. Tartaric Acid q.s. ad pH 3.0Phenol Anhydrous Water for Injection, U.S.P.

4.5 mgv 1.0 cc. 6O

q.s. ad

PROCEDURE 1. 2-(2-Benzoylphenyl)-2-imidazoline was slurried in part ofthe water for injection.

2. 2-(2-Benzoylphenyl)-2-imidazoline was solubilized by slowly addingthe tartaric acid to a pH of approximately 3.0.

3. The phenol anhydrous was then added.

4. The solution was filtered and allowed to stand for 24 hours. It wasthen filtered through an 02 Selas candle.

5. The solution was filled into desired size ampuls and sealed under anatmosphere of nitrogen.

6. All ampuls were inspected; those containing excessive amounts offibers were rejected.

The drug was prepared in duplex ampuls, one con- 0 taining the dry drugand the other containing the special diluent.

Dry Fill Ampul 5 cc.

2-( Z-benzoylphenyl)-2-imidazoline 25 mg.

A parenteral grade of the drug, fiber-free, was filled into the ampulusing a Diehl Mater electric filler or other suitable type filler. Theampuls were sealed and sterilized at 255F. for 2 hours.

Immediately before use the powder was solubilized with the followingsolution:

Special Diluent 2 cc.

per ml. Tartaric acid 16 mg. Water for Injection q.s. to 1.0 ml.

In a suitable container under an atmosphere of nitrogen the tartaricacid was dissolved in part of the water for injection. The solution wasmade to volume, filtered through an 02 Selas candle filter and filledinto 2 cc. flint ampuls. The filling should be done under an atmosphereof nitrogen. The ampuls were sealed and sterilized at 212F. for 30minutes. The ampuls were then inspected and those that leaked orcontained fibers were discarded. i

The drug in the preferred oral dosage form, i.e., tablets or capsulescontaining lO'to 25 mg. of active material, will be administered underordinary circumstances three or four times daily. The parenteralcomposition will be administered ordinarily one or two times daily.Effective dosages for the administration of compounds of this invention,i.e., the compounds of formulas I and II-d, will, of course, depend inall instances upon the severity and individual characteristics of eachcase as determined by the prescribing practitioner. It will beunderstood that dosage forms containing larger and smaller quantities ofthe active drug ingredient are encompassed by the scope of thisinvention and that such dosage forms can be administered more or lessfrequently than indicated heretofore. It will be understood that dosageforms containing inert adjuvants in quantities which are greater or lessthan those indicated heretofore are also encompassed by this invention.

The invention will be more fully understood from the examples whichfollow. These examples are illustrative of the invention and are not tobe construed as limitative thereof. All melting points are in degreescentigrade. Decomposition melting points were taken in a Thomas Hooverapparatus in open capillaries. They may vary depending on the rate ofheating.

EXAMPLE 1 Preparation of 2-benzoylbenzaldehyde A mixture of l g. ofselenium dioxide and l g. of Z-hydroxymethylbenzhydrol in 5 ml. ofacetic acid was refluxed for 4 /2 hours. The solution was cooled,filtered from selenium and the filtrate was poured into ice water andmade alkaline with sodium hydroxide. Extraction with ether gave a yellowoil to which petroleum ether was added. White prisms were obtained whichmelted at 6467. Ultraviolet maximum (2- propanol) at 226/7 my. (a15,750) and 251/2 my. (6 18,500), inflexion at 294 mp. (e 2600);infrared absorption (CHCl at 1665 cm and 1705 cm.

Anal. Calcd. for C I-1 2 C, 79.98; H, 4.79 Found: C, 80.00; H, 4.68

from about 60 to about 98 percent of the weight of the compositions inoral dosage form.

For parenteral administration the compounds can be formulated with aliquid diluent, for example, distilled water, in the preparation of asuitable parenteral dosage form. The preferred parenteral dosage formwill contain from about 0.5 mg. to about 15 mg. of the active drug. Ingeneral, the compounds of this invention are formulated withconventional inert adjuvants into dosage forms suitable for enteral orparenteral administration following the conventional techniques andprocedures of the prior art. Suitable dosage forms include tablets andcapsules as well as solutions, emulsions and suspensions. The inertadjuvants which are suitable for use in preparing the various dosageforms include liquids and solids inorganic or organic in nature such aswater, gelatin, lactose, starch, magnesium stearate, talc, vegetableoils, gums, polyalkylene glycols, Vaseline, etc. Additionally, thecompounds can be used in combination with preservatives, stabilizers,wetting or emulsifying agents, salts for altering the osmotic pressure,buffers, etc. If desired, the compounds can be used also inadmixturewith other therapeutically valuable substances. Specific embodimentsshowing illustrative formulations of an exemplary compound of for- .mulaI follow.

Tablet Formulation 1. 2-(Z-Benzoylphenyl)-2-imidazoline was mixed withthe lactose, corn starch, and pregelatinized corn starch in a suitablesize mixer.

2. The mix was passed through a Fitzpatrick Comminuting Machine fittedwith a No. 1A screen and with knives forward.

3. The mix was returned to the mixer and moistened with water to a thickpaste. The moist mass was passed through a No. 12 screen and the moistgranules were dried on paper-lined trays at 100F.

4. The dried granules were returned to the mixer, the calcium stearatewas added and mixed well.

5. The granules were compressed at a tablet weight of 200 mg, usingstandard concave punches having a diameter of /16 inch.

1 6 Suppository Formulation Per 1.3 Gram Suppository2-(2-benzoylphenyl)-2-imidazoline 0.025 gram Wecobee M (E. F. DrewCompany 1.230 gram 522 Fifth Avenue New York, New York) Carnauba Wax0.045 gram PROCEDURE 7 1. The Wecobee M and the camauba wax were meltedin a suitable size glass-lined container (stainless EXAMPLE 2Preparation of 2-(p-chlorobenzoyl)-benzaldehyde A solution of 18.6 g. of4-chloro-2-hydroxymethylbenzhydrol in ml. of acetic acid and 10.4 g.selenium dioxide was refluxed for 2 hours. The mixture was poured on iceand made alkaline and extracted with ether. Concentration of the ethersolution and addition of petroleum ether gave pale yellowprisms whichafter recrystallization from a mixture of ether and petroleum ether gave2-(p-chlorobenzoyl)-benzaldehyde melting at 1 12l 13. Ultravioletinflexion (2-propanol) at 225 my. (6 17,500) and maximum at 259 mp. (e22,500), infrared absorption (CHCl at 1670 cm and 1705 cm.

Anal. Calcd. for C H ClO C, 68.72; H, 3.71 Found. C, 69.12; H, 3.50

EXAMPLE 3 Preparation of 2-(p-anisoyl)-benzaldehyde A solution of 26 g.of 4-methoxy-2-hydroxymethylbenzhydrol in ml. of acetic acid and 14.5 g.selenium dioxide was refluxed for 2 hours. The mixture was filtered andthe filtrate was made basic. An oil separated which crystallized onstanding and was collected. Recrystallization from a mixture ofmethylene chloride and petroleum ether gave off-white platelets meltingat 909 1. Ultraviolet maxima (2-propanol) at 221 mu (6 21,600), 258 mp.(e 12,400) and 292 mp. (e 17,000); infrared absorption (CHCl at 1660 cmand at 1700 cm.

Anal. Calcd. for C, H O C, 74. 9;

9 H, 5.03 Found: C, 75.27; H, 5.26

EXAMPLE 4 Preparation of 2-benzoyl-4-chlorobenzaldehyde Anal. Calcd. forC H ClO- C, 6 2; H,

8.7 3.7 Found: C, 69.0 .8

To a stirred solution of 8.2 g. of lithium aluminum hydride in 180 ml.of tetrahydrofuran was added 40 g. of 2-(4-bromobenzoyl) benzoic acid inthe course of 30 minutes. The mixture, after being kept at 25 for 2hours, was cooled and 40 ml. of a saturated sodium sulfate solution wasadded slowly. The mixture was filtered and the filtrate concentrated.The resulting oily residue was dissolved in 32 ml. of acetic acid and 96ml. of xylene. This solution was added to a mixture of 17.1 g. ofselenium dioxide in 60 ml. of acetic acid and 120 ml. of xylene andrefluxed for 17 hours. During this time about 22 ml. of an aqueous phasehad collected in a Dean Stark receiver. The solution was filtered,washed with sodium hydroxide and concentrated. Addition of petroleumether gave white prisms melting at 103109. Recrystallization from amixture of ether and petroleum ether raised the melting point to 110113. Ultraviolet inflexion (2-propanol) at 225 mu (6 17,500) and maximumat 261 mp. (e 22,200); infrared absorption (CHCl at 1675 cm and 1705 cm.

Anal. Calcd. for C H BrO C, 58.16; H, 3.14 Found: C, 57.86; H, 3.41

EXAMPLE 6 Preparation of 2,3-dihydro-5-phenyl-5H-imidazo[2,l-a]isoindolesulfate from Z-benzoylbenzaldehyde A solution of 21 g. ofo-benzoylbenzaldehyde in 250 ml. of toluene and 34 ml. ofethylenediamine was refluxed for 24 hours. During this time 11.5 ml. ofan aqueous phase was separated in a Dean Stark receiver. The reactionmixture was concentrated in vacuo to an orange oil which was dissolvedin ethyl acetate and washed twice with water. The solution was dried andconcentrated, dissolved in 200 ml. of ethyl acetate and a solution of5.3 ml. of concentrated sulfuric acid in 100 ml. of ethanol was added. Acrystalline precipitate was collected which after recrystallization froma mixture of methanol and ethyl acetate gave white prisms melting at226-229 dec. Ultraviolet maxima (2- propanol) at 240 mp. (e 15,000) and276 mu (6 5,400); infrared absorption (KBr) 1660 cm.

Anal. Calcd. for C H N H 50 C, 57.8 Found: C, 57.6

ene, white prisms melting at 226228 dec. were obtained. Nmr peaks (DMSO)at 8 3.6-4.6 (4H, multiplet), at 8 6.13 (1H, singlet), at 8 7.3-7.9 (9H,multiplet).

EXAMPLE 7 Preparation of 2,3-dihydro-5-phenyl-5H-imidazo[2,l-a]isoindolesulfate from 2-(2-aminoethy1)-3-phenylphtha1imidine A solution of 1.2ml. of titanium tetrachloride in 30 ml. of xylene was added at 25 to astirred solution of 2.5 g. of 2-(Z-aminoethyl)-3-phenylphthalimidine inml. of xylene. The mixture was refluxed for 18 hours, cooled and washedwith an aqueous solution of sodium carbonate. The xylene solution wasextracted with 2N hydrochloric acid. The acidic extract was poured onice and made alkaline with sodium hydroxide. The solution was extractedwith ethyl acetate and the extract was concentrated. Addition of asolution of sulfuric acid in a mixture of ethanol and tetrahydrofuranand further dilution with ethyl acetate gave a crystalline precipitate.Recrystallization from a mixture of methanol and ethyl acetate gave theproduct as white prisms melting at 225228 dec.

EXAMPLE 8 Preparation of 2,3-dihydro-5-hydroperoxy-S-phenyl-SH-imidazo-[2,1-a]isoindo1e The base liberated from 16.6 g. of 2,3-dihydro-5-pheny1-5H-imidazo[2,1-a]isoindole sulfate was dissolved in 50 ml. ofethanol and l 1 ml. of a 30 percent by weight aqueous solution ofhydrogen peroxide was added. The mixture was stirred at 25 for 40 hours.A

crystalline crop was collected and placed on a column containing 250 g.of silica gel. Elution with a mixture of 1 part of methanol (volume) and1 part of chloroform (volume) gave fractions from which on concentrationa crystalline residue was obtained. Recrystallization from a mixture ofmethanol and chloroform gave the product as white prisms melting at167l68 dec. Ultraviolet inflexions (2-propano1) at 232 my. (6 14,000)and 290 my. (6 2600), maxima at 269 mp. (e 4000) and 275 my. (6 4400),infrared absorption (KBr) at 1665 cm".

Anal. Calcd. for CWHHNZOZ: c, 72.16; 11, 5.30; N, 10.52 Found: c,7209;11, 5.39; N, 10.22

The hydrochloride of 2,3-dihydro-5-hydroperoxy-5-phenyl-5H-imidazo[2,1-a]isoindole was prepared with methanolic hydrogenchloride and after recrystallization from a mixture of methanol andether gave white platelets melting at 158-l59 dec. Ultraviolet maxima(2-propano1) at 245 mp. (e 14,800) and 278 mu (6 5200); infraredabsorption (KBr) at 1680 cm.

3.47; Found: C, 63.63'

Cl, 11.71 ,Cl, 1 .79

EXAMPLE 9 Preparation of S-(p-chlorophenyl)-2,3-dihydro--hydroperoxy-5H-imidazo[2,l-a]isoindole hydrochloride 1 Gram of2-(p-chlorobenzoyl)-benzaldehyde was 5 thoroughly mixed with 0.9 g. ofethylenediamine toluene sulfonate and heated in a metal bath (bathtemperature, l125) for 1 minute. On cooling a deep yellow glassymaterial was obtained which on addition of methylene chloride, ethylacetate and petroleum ether gave a crystalline precipitate which wastreated with ice cold aqueous sodium hydroxide. The mixture was ex-.

tracted with ether and the extract was exposed to air at for 18 hours. Acrystalline crop was collected and suspended in methylene chloride.Addition of ethereal hydrogen chloride gave a crystalline material whichafter recrystallization-from a mixture of methanol and ether gave whiteprisms melting at 175177 dec. U1- traviolet infiexion (2-propanol) at223 my. (6 21,800) and 279 my. (6 5600), maximum at 243 mpt (e 15,500);infrared absorption (KBr) at 1670 cm.

Anal Calcd. for c,.,H,,c1N o,.Hc1; c, 56.99; H, 4.18;

CI, 21.03; N, 8.31

Found: C, 57.14; H, 4.15;

Cl, 21.02; N, 8.30

EXAMPLE 10 Preparation of 2-(2-benzoy1phenyl)2-imidazoline from2,3-dihydro-5-phenyl-5H-imidazo[2,1-a]isoindole To a suspension of 8.5g. of 2,3-dihydro-5-phenyl- 5l-l-imidazo[2,l-a]isoinc1ole sulfate inwater was added 50 ml. of 1N aqueous sodium hydroxide. Extraction.

with methylene chloride and concentration gave an orange oil which wasdissolved in a mixture of, ml. of methylene chloride and 30 ml.of'ethanol. To this solution was added 2.3 ml. of 30 percent by weighthydrogen peroxide. After stirring at 25 for 18 hours, a precipitate wascollected which after recrystallization from methanol gave white prismsmelting at 194l96 dec. Ultraviolet inflexions (2-propanol) at 225 mp. (e15,500) and 290 mp. (e 2250), maxima at 269 my. (6 4100) and 276 mp. (e4250); infrared absorption (KBr) 1660 cm.

Anal. Calcd. for C H N O: C, 76.78, H, 5.64; N, 11.19

Found: C, 76.42; H, 5.79, N, 11.13

Anal. Calcd. for c H N Oj-lclz C1, 12.36 Found: Cl, 12.22

The hydrobromide was prepared by adding an aqueous solution ofhydrobromic acid to a suspension of 2-(2-benzoylphenyl)-2-imidazoline inethanol. Addition of ether gave a precipitate which afterrecrystallization from a mixture of ethanol and ether gave whiteplatelets melting at 193-194 dec.

Anal. Calcd. for C ,H, N O.HBr: Br, 24.13 Found: Br, 24.15

EXAMPLE 1 1 Preparation of 2-(2-benzoylphenyl)-2-imidazoline from2,3-dihydro- 5hydroperoxy-5-phenyl-5H-imidazo[2,1a]isoindole A solutionof 0.7 g. of sodium sulfite heptahydrate in 3 m1. of water was added to0.5 g. of 2,3-dihydro-5- hydroperoxy-S-phenyl-5H-imidazo[2,1-a]isoindolein 7 ml. of dimethylformamide. The solution was heated to 100 for 15minutes. On cooling and addition of 20 ml. of water,2-(2-benzoylphenyl)-2imidazoline was obtained.

EXAMPLE 12 Preparation of 2-(2-benzoylphenyl)-2-imidazoline from I2,3-dihydro- S-hydroperoxy-S-phenyl-5H-imidazo[2, l-a]isoindo1e Asolution of 0.1 g. of 2,3-dihydro-5-hydroperoxy-5-phenyl-5l-l-imidazo[2,1-a]isoindole and 0.33 g. of triethylphosphite in20 ml. of ethanol was kept on a steam bath for 5 minutes, then 18.hoursat 25. The solution was concentrated in vacuo and'on addition of water2- (2-benzoylphenyl)-2-imidazoline was obtained.

EXAMPLE 13 Preparation of 2-(2-benzoylphenyl)-2-imidazo1ine from 2-(2-aminoethyl)- 1 -phenylisoindoline A solution of 3.3 g. of chromiumtrioxide and 5.9 g. of 2-(2-aminoethyl)-l-phenylisoindoline in 250 ml.of acetic acid was stirred at 5560 for 18 hours. The solution wascooled, poured on ice and made alkaline. Extraction with methylenechloride and removal of the solvent gave a brown oil which partlycrystallized. Recrystallization from a mixture of chloroform and ethylacetate gave the product as white prisms melting at 194196 dec. 7

EXAMPLE 14 Preparation of 2-(2-aminoethyl)-l-phenylisoindoline Asolution of 127 g. (0.59 mole) of 2-hydroxymethylbenzhydrol wasdissolved in 900 ml. of benzene, g. of anhydrous magnesium sulfate wasadded and the mxture was cooled in an ice bath. Hydrogen bromide wasbubbled into the stirred solution until saturation which took about 30minutes. During this time the temperature of the solution was kept at15l8. The ice bath was removed and the temperature was allowed to riseto 35 in the course of 1 hour. The mixture was heated for another hourat 40-45 on a steam bath. During the whole time hydrogen bromide waspassed into the solution to keep it saturated. The mixture was filteredand the solution was concentrated in vacuo to give a red oil which wasdissolved in 200 ml. of benzene and added to 342 g. (5.7 moles) ofethylenediamine in the course of 15 minutes. During the addition themixture was stirred and cooled to maintain a temperature of ca. 40 Themixture was stirred at 25 for 70 minutes. Two layers were obtained andseparated. The,

benzene layer was washed with water and concentrated in vacuo. Theresidual oil was dissolved in 250 ml. of ether. This solution wasextracted twice with 300 ml. of cold 1N hydrochloric acid. The acidicaqueous phase was made alkaline with aqueous sodium hydroxidee andextracted with 350 ml. of ether. The ethereal solution was washed with250 ml. of water, dried and concentrated. The residue was an amber oilwhich crystallized on scratching. This material melted up to ca. 45. Byanalogy there were also prepared the following: 2-( 3-aminopropyl l-phenylisoindoline 2-(2-aminoethyl)-6-chloro-1-phenylisoindoline2-(2-aminoethyl)-1-(p-methoxyphenyl)isoindoline 2-( 4-aminobutyl 1-phenylisoindoline 2-(2-amino-2-methylpropyl)-1-phenylisoindoline 2-(2-aminopropyl 1 -phenylisoindoline2-(2-aminoethyl)-1-(p-hydroxyphenyl)isoindoline.

EXAMPLE 15 Preparation of 2-[2'-(4-chlorobenzoyl)phenyl]-2-imidazolineTo 1 ml. of ethylenediamine was added 1 g. of2-(pchlorobenzoyl)-benzaldehyde in small portions. An exothermicreaction took place and after minutes the reaction mixture was pouredinto ice water. A yellow solid precipitate was collected and dissolvedin methylene chloride. Ether and petroleum ether were added and thesolution was shaken in air at 25. A crystalline precipitate was obtainedwhich after recrystallization from a mixture of methylene chloride andmethanol gave white needles melting at 178-1 80 dec. Ultraviolet maxima(Z-propanol) at 223 mp (e 21,250), 268 mp (e 4300), 275 mp (e 4320),inflexion at 290 mp (e 2200); infrared absorption (KBr) at 1660 cm.

Anal. Calcd. for c u cm o C, 67.49; Found: C, 67.38;

and ether to give white prisms melting at l68171 65 dec. Ultravioletinflexion (2-propanol) at 220 mp (e 22,000), maxima at 252 mp 12,900),266 mp (e 13,000); infrared absorption (KBr) at 1670 cm.

Anal. Calcd. for C H ClN QHClz Cl, 22.08 Found: Cl, 22.18

EXAMPLE 16 Preparation of 2-[2'-(4-anisoyl)phenyl]-2 imidaz0line To 4ml. of ethylenediamine was added 2 g. of 2-(p- 1O anisoyl)benzaldehydein small portions. The solution was stirred for minutes, poured into icewater and extracted with methylene chloride. The methylene chloridesolution was concentrated, the residue was dissolved in ethanol and astream of air was passed through the solution for 18 hours. Acrystalline precipitate was collected and after recrystallization from amixture of chloroform and ether gave white prisms melting at 17l-174dec. Ultraviolet maxima (2- propanol) at 227 mp (e= 20,200), 277 mp (e=8800), 282 mp (e 8750), inflexion at 292 mp (e 7200); infraredabsorption (KBr)-at 1660 cm.

Anal. Calcd. for C I-1 N 0 C, 72.84; H, 5 H 5 Found: c, 73.07;

EXAMPLE 17 Preparation of '2-[4-chloro-2'-benzoylphenyl]-2imidazoline To2 ml. of ethylenediamine was added 0.9 g. of 2-benzoyl-4-'chlorobenzaldehyde in small portions. The solution wasstirred for 10 minutes, poured into ice water and the solid yellowprecipitate was collected. This solid was dissolved in ether and shakenin air for 45 minutes. A white precipitate was obtained which afterrecrystallization from a mixture of methylene chloride and methanolmelted at 200-202 dec. Ultraviolet maxima (2-propanol) at 242 mp (e17,500), 278 mp (e 3800), 286 mp (e 3300), inflexions at 270 mp (e3450), 295 mp (e 2400); infrared absorption (KBr) at 1665 cm Anal.Calcd. for C H CIN O: C, 67.49; H, 4.60 Found: C, 67.42; H, 4.90

The 2-[4chloro-2'-benzoylphenyl]-2-imidazoline prepared in this mannercan form the isomeric 7-chloro-2,3-dihydro-5- hydroxy-S-phenyl-5H-imidazo[2,1-a]isoindole.

EXAMPLE 18 Preparation of 2-[ 2-( 4-bromobenzoylphenyl -2-imidazoline Asolution of 6 g. of 2-(4-bromobenzoyl)- benzaldehyde and 6.6 ml. ofethylenediamine in 50 ml. of toluene was refluxed for 18 hours. Duringthis time 0.5 ml. of an aqueous phase had separated in a Dean Starkreceiver. The mixture was concentrated in vacuo and the residual orangeoil was dissolved in a mixture containing 15 ml. of ethanol, 15 ml. ofmethylene chloride and 1.5 ml. of a 30 percent by weight aqueoussolution of hydrogen peroxide. After stirring at 25 for 18 hours a whiteprecipitate was collected which after recrystallization from methanolgave white needles melting at l87-189 dec. Ultraviolet maxima(2-propanol) at 227 mu (6 22,800), 259 mp. (e 4700), 275 mp (e 4800),inflexion at 292 mp (e 2300); infrared absorption (KBr) at 1660 cm.

Anal. Calcd. for C H BrN O: C, 58. Found: C, 58.

Anal. Calcd. for C ,H, BrN O.HCl: Cl, 9.70 Found: Cl, 9.82

EXAMPLE 19 Preparation of 2,3-dihydro-5-methoxy-5-phenyl-5H-imidazo[2, l-a]- isoindole hydrochloride A solution of 5 g. of2-(2-benzoylphenyl)-2- imidazoline in ml. of methanol was refluxed for18 hours. The solution was concentrated in vacuo, dissolved in 20 ml. ofmethanol and 60 ml. of ether was added. Crystals precipitated and wereidentified as starting material. The mother liquor was concentrated andthe residue was recrystallized from a mixture of methanol, methylenechloride and ether to give the product as white prisms melting at139-141 dec. Ultraviolet maxima (2-propanol) at 244 mp. (e 14,400) and278 mp. (e 5100); infrared absorption (KBr) at 1670 cm.

Anal. Calcd. for C H N O.HCl: C, 67.83; H, 5.70;

OCH 10.32

Found: C, 67.84; H, 5.61;

OCH 10.44

The corresponding base was obtained as a colorless oil by liberating itfrom the hydrochloride obtained as above with alkali. Ultravioletinflexions (0.1N KOH)) at 230 mp. (e 4600). 290 mp. (e 2700), maxima at269 mp. (e 4200) and 275 mp. (e 4600).

24 Infrared absorption (smear) at 1660 cm and nmr peaks (CDCl at 8 3.12(3H, singlet, OCH 8 2.6-3.5 (2H, multiplet, N-CH 8 4.2-4.5 (2H,multiplet, =N-CH 8 7.1-8.0 (9H, multiplet, aromatic CH).

EXAMPLE 20 Preparation of 2 ,3,4,6-tetrahydro-6-phenylpyrimido[2,1-a]isoindole sulfate A solution of10.5 g. of 2-benzoylbenzaldehyde and 22 ml. of propylenediamine in 125ml. of toluene was refluxed for 18 hours. During this time 4.5 ml. of anaqueous phase had separated in a Dean Stark receiver. The solution wasconcentrated in vacuo and the residue was recrystallized from a mixtureof ethanol and petroleum ether to give white prisms melting at ll72 dec.Ultraviolet maximum (2-propano1) at 238 mp. (e 18,200), inflexions at246 mp. (e 16,000), 265 mp. (e 5600), 276 mp. (e 3400) and 285 mp. (e2100); infrared absorption (KBr) at 1675 cm'.

EXAMPLE 21 Preparation of 2,3,4,5-tetrahydro-7-hydroxy-7-phenyl-7H-diazepino[ 2, 1-a]isoindole A solution of 10.5 g. of2-benzoylbenzaldehyde and 28.5 ml. of 1,4-diaminobutane in ml. oftoluene was refluxed for 18 hours. During this time 2.5 ml. of anaqueous phase had separated in a Dean Stark receiver. The solution wasexposed to air for 60 hours, concentrated and diluted with 300 ml. ofcarbon tetrachloride. A crystalline precipitate was obtained which wassuspended in 40 ml. of ethanol. A solution of 1.9 g. of oxalic acid in40 ml. of methanol was added and the solution was concentrated anddiluted with ether. The precipitate was collected and recrystallizedfrom a mixture of methanol and ether to give the oxalic acid salt aswhite prisms melting at ca. 200 dec. This salt was suspended in amixture of aqueous sodium carbonate solution and methylene chloride. Themethylene chloride solution was concentrated and the residue wasrecrystallized from a mixture of chloroform and ether to give theproduct as white needles melting at 216-220 dec. Ultraviolet maxima(2-propanol) at 258 mp. (e 5000), 265 mp. (e 5100), 273 mp. (e

4800), inflexions at 230 mp. (e 15,000), 290 mp. (e 2400); infraredabsorption (KBr) at 1650 cm.

Anal. Calcd. for C H N O: C, 77.67; H, 6 Found: C, 77.64; H, 6

EXAMPLE 22 Preparation of 2-(2-aminoethy1)-3-phenylphthalimidine ofacetic acid containing 2.5 g. of hydrogen chloride was shaken under oneatmosphere of hydrogen at 25 using 0.5 g. of platinum oxide as catalyst.in the course of 7 hours, 3000 ml. of hydrogen (theory ca. 2500 ml.) wasabsorbed and the rate of uptake had slowed down considerably. Thesolution was poured into ice water, basified with ammonia and extractedwith methylene chloride. The organic phase was dried and concentrated.The residue crystallized with ether and after recrystallization from amixture of methylene chloride and petroleum ether gave white prisms of2-(2- aminoethyl)-3-phenylphthalimidine melting at 90-93. m 1685 cm, g-247 mu, 6 6000, 279 mu, 1900.

Anal. Calcd. for C, H, N O: C, 76.16; H, 6.39 Found: C, 75.81' H, 6.32

EXAMPLE 23 Preparation of 2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline to250 ml. of concentrated sulfuric acid was added, with stirring andslight cooling, 37.5 g. (0.545 mole) of sodium nitrite. To this wasadded 120.5 g. (0.50 mole) of 2-( 2-aminobenzoyl)benzoic acid at such arate that the temperature of the reaction mixture remained between30-40. After the addition was complete the reaction mixture was stirredfor one hour and then poured into one liter of ice and water andfiltered. The filtrate was added rapidly to a stirred solution of 55 g.(0.555 mole) of cuprous chloride, 150 g. of sodium chloride, 250 ml. ofconcentrated hydrochloric acid and 300 ml. of water. The precipitatedgum was extracted with chloroform and the extracts were washed twicewith water, dried over anhydrous sodium sulfate and evaporated undervacuo to leave a red oil which crystallized upon scratching.Recrystallization from 200 ml. of ethyl acetate gave 2-(2-chlorobenzoyl)benzoic acid as a pink solid. A sample recrystallizedthree times from ethyl acetate gave col orless prisms, double m.p.112-l16 and 124l26.

To a stirred suspension of 22.8 g. (0.60 mole) of lithium aluminumhydride in 700 ml. of dry tetrahydrofuran was added 104 g. (0.40 mole)of 2-(2- chlorobenzoyl)benzoic acid prepared as above in portionskeeping the reaction mixture temperature between 1530 with ice cooling.After the addition was complete the reaction mixture was stirred for onehour. Ether (400 ml.) was added followed by the slow addition of 80 ml.of water, with ice cooling. The mixture was filtered through a largesintered glass funnel which contained a matting of Celite filter-aid.The filtered solids were washed with tetrahydrofuran and the combinedfiltrates were evaporated under vacuo to a yellow oil which crystallizedupon scratching. The material was recrystallized from 150 ml. ofisopropyl ether to give 2-chloro-2'-hydroxymethylbenzhydrol as aslightly pink solid, m.p. 8587. A sample was recrystallized three timesfrom isopropyl ether to give colorless prisms, m.p. 8687.

A 2-liter, 3-necked, round bottomed flask was fitted with a mechanicalstirrer, dropping funnel and a Dean- Stark trap fitted with a condenser.A mixture of 41.7 g. (0.376 mole) of selenium dioxide in 150 ml. ofacetic acid and 300 ml. of xylene was refluxed for 15 minutes. To theboiling mixture was added dropwise during one hour, a solution of 74.4g. (0.3 mole) of 2chloro-2'- hydroxymethylbenzhydrol prepared as abovein 85 ml. of acetic acid and 250 ml. of xylene. The Dean-Stark trap wascooled during this time to promote separation of an aqueous phase. About60 ml. of the aqueous phase was separated during 5 hours. The reactionmixture was refluxed for a total of 22 hours, cooled and filtered. Thefiltrate was added to 800 ml. of ice and water, make alkaline with 50percent sodium hydroxide and the mixture extracted with 600 ml. ofether. The extracts were washed with water, dried over anhydrous sodiumsulfate and evaporated to yield an orange oil which could not becrystallized. Vapor phase chromatographic analysis showed the presenceof two compounds.

45.4 Grams of the oil, 52.5 g. (0.875 mole) of ethylenediamine and 400ml. of benzene were refluxed for 5 hours in a round bottomed flaskequipped with a Dean-Stark trap and a condenser. About 6 ml. of aqueousphase separated in the trap. The reaction mixture was cooled, washedthree times with saturated aqueous salt solution and dried overanhydrous sodium sulfate. Air was then bubbled through the benzenesolution for 15 hours but only a small amount of solid separated.

The benzene was removed under vacuo and the residue was dissolved in ml.of ethanol and 40 ml. (0.350 mole) of 30 percent hydrogen peroxide.After stirring for 3 hours the ethanol was removed under vacuo and 300ml. of benzene was added to the residue. The aqueous phase was separatedand the benzene solution was dried over anhydrous sodium sulfate andevaporated under vacuo to leave a pale yellow oil. Ether (150 ml.) wasadded and a crystalline solid separated. The mixture was filtered togive a pale yellow solid, m.p. l64l67 dec. The ether filtrate wasstirred at room temperature, exposed to air, for two days. Theprecipitated solid was filtered 'to give an additional pale yellowsolid. Thin layer chromatography of the combined solids showed thepresence of one major component, Rf 0.41, and a minor component, Rf0.67. The latter component was2,3-dihydro-5-hydroperoxy-5-(ochlorophenyl)-5H-imidazo[2,1-a]isoindolesince the yellow solid precipitated iodine from a saturated methanolicpotassium iodide solution.

To a suspension of the yellow solid in 60 ml. of refluxing methanol wasadded a solution of 4.28 g. (0.017 mole) of Na SO .7l-l O in 30 ml. ofwater over a period of 5 minutes. After refluxing for 15 minutes longerthe reaction mixture was cooled and filtered. The filtered solid waswashed 3 times with 20 ml. of water and dried. Recrystallization frommethanol-chloroform gave 2-[2-(2-ch1orobenzoyl)phenyl]-2-imidazoline ascolorless prisms, m.p. l8l dec.

Anal. Calcd. for C H CIN O: C, 67. Found: C, 67.

The 2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline prepared in this mannercan form the isomeric 2,3-dihydro-5-hydroxy-5-(2'-chlorophenyl)-5H-imidazo[2,1-a]isoindole.

To a hot solution of 6.0 g. (21.2 mmoles) of 2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline in 25 ml. of 6 N methanolic hydrogenchloride and 35 ml. of methanol was added 200 ml. of ether and thesolution cooled. Filtration 7 gave 2-[ 2-( 2-chlorobenzoyl)phenyl]-2-imidazoline hydrochloride,

m.p. l78-l80 dec. Dilution of the mother liquors.

were 200 ml. of ether followed by cooling and filtering afforded anadditional quantity of hydrochloride. Recrystallization frommethanol-ether gave colorless prisms, m.p. l78l80 dec.

Anal. Calcd. for C H Cl N O: Cl, 22.08 Found: Cl, 22.00

EXAMPLE 24 Preparation of 2-(2-benzoylphenyl)-2-imidazoline via 7 1,2,3,9b-tetrahydro-5l-l-imidazo,[2,1-a]isoindol-5 -one A solution of 7.5 g.of phthalaldehydic acid in 30 ml. of ethanol and 34 ml. ofethylenediamine was refluxed for 16 hours. The solution was concentratedin vacuo and the residue was dissolved in methylene chloride. Thesolution was washed with water, dried and concentrated. The residue wasdistilled in a bulb tube at 0.3 mm at a bath temperature of l50l 80. Acolorless oil was obtained which was dissolved in methanol and onaddition of ethereal hydrogen chloride gave white prisms of 1,2,3,9btetrahydro-5H-imidazo[2,l-a]isoindol-5-one hydrochloride, m.p.222-224 dec.

The salt obtained in the preceding experiment was treated with aqueouspotassium carbonate solution. Extraction with methylene chloride gave anoil of which and ml. of ether. To this solution was added 5.5 ml. of a 2N solution of phenyl lithium in a mixture of benzene and ether (7:3).After stirring at 25 for 1 hour the solution was poured into ice waterand extracted with ethyl acetate. This solution was concentrated and theresidue was exposed to air for 48 hours. On addition of methylenechloride crystals were obtained which were dissolved in methanol.Addition of ethereal hydrochloric acid gave white prisms which afterrecrystallization from a mixture of methanol and ether gave crystalsmelting at l73175 dec. This material was identical with authentic2-(2-benzoylphenyl)-2-imidazoline hydrochloride.

We claim:

1. A process for the preparation of a compound of the formula 0.9 g. wasdissolved in a mixture of 25 ml. of benzene and its tautomer of theformula wherein B represents an alkylene chain of 2 to 4 carbon atoms inwhich one or more of the hydrogens can be replaced by straight chainlower alkyl of l to 6 carbon atoms; and R R R and R are eachindependently selected from the group consisting of hydrogen, halogen,straight chain lower alkyl of 1 to 6 carbon atoms, lower alkoxy of l to6 carbon atoms, hydroxy and trifluoromethyl which comprises treating acompound of the formula:

oxidizing agent is chromium trioxide.

1. A PROCESS FOR THE PREPARATION OF A COMPOUND OF THE FORMULA
 2. Aprocess in accordance with claim 1, wherein B is ethylene; R1, R2 and R3are hydrogen; and R4 is hydrogen or chlorine.
 3. A process in accordancewith claim 2, wherein the oxidizing agent is air.
 4. A process inaccordance with claim 2, wherein the oxidizing agent is gaseous oxygen.5. A process in accordance with claim 2, wherein the oxidizing agent ischromium trioxide.